RNF146

Summary

RNF146 (ring finger protein 146, HGNC:21336) is a protein-coding gene on chromosome 6q22.33, encoding E3 ubiquitin-protein ligase RNF146 (Q9NTX7). E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation.

Enables poly-ADP-D-ribose binding activity and ubiquitin-protein transferase activity. Involved in positive regulation of canonical Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleoplasm; and plasma membrane.

Source: NCBI Gene 81847 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_001242850

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21336
Approved symbol	RNF146
Name	ring finger protein 146
Location	6q22.33
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434O1427, dactylidin, dJ351K20.1
Ensembl gene	ENSG00000118518
Ensembl biotype	protein_coding
OMIM	612137
Entrez	81847

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000356799, ENST00000368314, ENST00000476956, ENST00000477776, ENST00000480444, ENST00000489534, ENST00000495188, ENST00000608340, ENST00000608991, ENST00000609447, ENST00000609944, ENST00000610153, ENST00000610162, ENST00000911117, ENST00000911118, ENST00000917447

RefSeq mRNA: 10 — MANE Select: NM_001242850 NM_001242844, NM_001242845, NM_001242846, NM_001242847, NM_001242848, NM_001242849, NM_001242850, NM_001242851, NM_001242852, NM_030963

CCDS: CCDS5136, CCDS56449

Canonical transcript exons

ENST00000368314 — 3 exons

Exon	Start	End
ENSE00001446854	127286616	127288562
ENSE00001446857	127266864	127266925
ENSE00003708746	127280231	127280340

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9592 / max 358.8404, expressed in 1805 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69709	15.1470	1785
69710	8.7632	1743
204198	0.0490	19

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.54	gold quality
cerebellar cortex	UBERON:0002129	98.06	gold quality
cerebellar hemisphere	UBERON:0002245	98.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.82	gold quality
cerebellum	UBERON:0002037	97.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.65	gold quality
mucosa of stomach	UBERON:0001199	96.56	gold quality
tibia	UBERON:0000979	96.55	gold quality
biceps brachii	UBERON:0001507	96.43	gold quality
middle temporal gyrus	UBERON:0002771	96.23	gold quality
tendon	UBERON:0000043	96.18	gold quality
body of uterus	UBERON:0009853	96.18	gold quality
calcaneal tendon	UBERON:0003701	96.09	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.06	gold quality
tendon of biceps brachii	UBERON:0008188	96.02	gold quality
muscle of leg	UBERON:0001383	96.01	gold quality
gastrocnemius	UBERON:0001388	96.00	gold quality
monocyte	CL:0000576	95.99	gold quality
cortical plate	UBERON:0005343	95.99	gold quality
right lung	UBERON:0002167	95.96	gold quality
endocervix	UBERON:0000458	95.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.86	gold quality
right lobe of thyroid gland	UBERON:0001119	95.83	gold quality
medial globus pallidus	UBERON:0002477	95.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.75	gold quality
left lobe of thyroid gland	UBERON:0001120	95.68	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.62	gold quality
mononuclear cell	CL:0000842	95.57	gold quality
caput epididymis	UBERON:0004358	95.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.55	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting RNF146, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 15)

• Dactylidin may function early in the progression of Alzheimer’s disease. (PMID:15813938)
• Mutations in the coding regions of the RNF146 and ECHDC1 genes do not contribute to the burden of inherited predisposition of breast cancer in Ashkenazi high risk women. (PMID:19517271)
• RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins (PMID:21799911)
• Iduna is a Poly(ADP-ribose)-dependent ubiquitin E3 ligase. (PMID:21825151)
• the RNF146 WWE domain recognizes poly(ADP-ribose) (PAR) by interacting with iso-ADP-ribose (iso-ADPR), the smallest internal PAR structural unit containing the characteristic ribose-ribose glycosidic bond formed during poly(ADP-ribosyl)ation. (PMID:22267412)
• RNF146/Iduna has been found to be implicated in neurodegenerative disease and cancer development. [Review] (PMID:22274711)
• RNF146 regulated the development and progression of NSCLC (PMID:24454854)
• the maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146-TNKS complex, which in turn regulates the homeostasis of PARylation-dependent ubiquitination activity in the cell (PMID:25327252)
• Iduna expression under disruptive neurohomeostasis (e.g., uncompensated oxidative stress or ischemic stroke after MCAo) is upregulated by neuroprotectin D1 and thus serves as a key regulator of cell survival, halting neural cell death. (PMID:28430183)
• RNF146 exerted oncogenic role through ubiquitination of Axin1 to activate beta-catenin signaling. (PMID:29932918)
• Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERbeta activity and RNF146 expression. (PMID:30974833)
• Proteome-wide Analysis Reveals Substrates of E3 Ligase RNF146 Targeted for Degradation. (PMID:32958691)
• Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs. (PMID:34128958)
• Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation. (PMID:35733260)
• SUMOylation of RNF146 results in Axin degradation and activation of Wnt/beta-catenin signaling to promote the progression of hepatocellular carcinoma. (PMID:37029301)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf146	ENSDARG00000089981
mus_musculus	Rnf146	ENSMUSG00000038876
rattus_norvegicus	Rnf146	ENSRNOG00000011588
drosophila_melanogaster	Rnf146	FBGN0036897
caenorhabditis_elegans	Y105E8A.14	WBGENE00013674
caenorhabditis_elegans		WBGENE00015324

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF146 — Q9NTX7 (reviewed: Q9NTX7)

Alternative names: Dactylidin, Iduna, RING finger protein 146, RING-type E3 ubiquitin transferase RNF146

All UniProt accessions (3): A0A0G2JLL7, Q9NTX7, V9GYY4

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation. May regulate many important biological processes, such as cell survival and DNA damage response. Acts as an activator of the Wnt signaling pathway by mediating the ubiquitination of PARsylated AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex. Acts in cooperation with tankyrase proteins (TNKS and TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, BLZF1, CASC3, TNKS and TNKS2. Recognizes and binds tankyrase-dependent PARsylated proteins via its WWE domain and mediates their ubiquitination, leading to their degradation. Different ubiquitin linkage types have been observed: TNKS2 undergoes ubiquitination at ‘Lys-48’ and ‘Lys-63’, while AXIN1 is only ubiquitinated at ‘Lys-48’. May regulate TNKS and TNKS2 subcellular location, preventing aggregation at a centrosomal location. Neuroprotective protein. Protects the brain against N-methyl-D-aspartate (NMDA) receptor-mediated glutamate excitotoxicity and ischemia, by interfering with PAR-induced cell death, called parthanatos. Prevents nuclear translocation of AIFM1 in a PAR-binding dependent manner. Does not affect PARP1 activation. Protects against cell death induced by DNA damaging agents, such as N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest. Promotes cell survival after gamma-irradiation. Facilitates DNA repair.

Subunit / interactions. Can form homooligomers. Interacts with PARsylated AXIN1, AXIN2, BLZF1, CASC3, H1-2, IPO7, LIG3, NCL, PARP1, XRCC1, XRCC5 and XRCC6. Interacts with DDB1, DHX15, IQGAP1, LRPPRC, PARP2, PRKDC, RUVBL2, TNKS1 and TNKS2. Binding often leads to interactor ubiquitination, in the presence of the appropriate E1 and E2 enzymes, and proteasomal degradation.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Tissue specificity. Ubiquitously expressed. Up-regulated in brains from patients with Alzheimer disease.

Post-translational modifications. Ubiquitinated; autoubiquitinated. Polyubiquitinated in the presence of UBE2D1, UBE2D2 and UBE2D3. Multimonoubiquitinated in the presence of UBE2E1. Not ubiquitinated in the presence of UBE2H, CDC34, UBE2L3, UBE2L6, nor UBE2C. In the absence of PAR, autoubiquitination occurs on Lys-85, Lys-95 and Lys-176 via ‘Lys-11’ and ‘Lys-48’ ubiquitin linkages. In the presence of PAR, Lys-131 and Lys-176 are ubiquitinated via ‘Lys-6’, ‘Lys-33’ and ‘Lys-48’ ubiquitin linkages. Autoubiquitination is enhanced upon PAR-binding.

Disease relevance. Defects in RNF146 are a cause of susceptibility to breast cancer.

Domain organisation. The WWE domain mediates non-covalent PAR-binding.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Was named dactylidin after the Greek term ‘daktylidi’ for ring, ’the thing around the finger’. Was named Iduna after the Norse goddess of protection and eternal youth.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NTX7-1	1	yes
Q9NTX7-2	2

RefSeq proteins (10): NP_001229773, NP_001229774, NP_001229775, NP_001229776, NP_001229777, NP_001229778, NP_001229779, NP_001229780, NP_001229781, NP_112225 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR004170	WWE_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018123	WWE-dom_subgr	Domain
IPR033509	RNF146	Family
IPR037197	WWE_dom_sf	Homologous_superfamily
IPR044110	RING-HC_RNF146	Domain

Pfam: PF02825, PF13920

UniProt features (54 total): strand 12, mutagenesis site 10, binding site 7, sequence conflict 6, cross-link 4, helix 3, modified residue 2, compositionally biased region 2, turn 2, chain 1, domain 1, splice variant 1, zinc finger region 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3V3L	X-RAY DIFFRACTION	1.65
6CF6	X-RAY DIFFRACTION	1.93
2D8T	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTX7-F1	68.11	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 154; 164; 176; 108; 111; 115; 145

Post-translational modifications (6): 290, 294, 85, 95, 131, 176

Mutagenesis-validated functional residues (10):

Position	Phenotype
54	partially suppression of wnt3a signaling and stabilization of axin1, tnks and tnks2 with or without wnt3a induction. no
106	no effect on wnt signaling pathway.
108	loss of iso-adp-ribose-binding.
111	minor effect on iso-adp-ribose-binding.
115	strong decrease in iso-adp-ribose-binding affinity.
145	loss of iso-adp-ribose-binding.
154	loss of iso-adp-ribose-binding affinity.
163	abolishes the ability to recognize and bind parsylated proteins.
164	loss of iso-adp-ribose-binding.
176	minor effect on iso-adp-ribose-binding.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-4641257	Degradation of AXIN
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8948751	Regulation of PTEN stability and activity
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-6807070	PTEN Regulation
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 132 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, AAAYRNCTG_UNKNOWN, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, USF_01, GOBP_PROTEIN_AUTOUBIQUITINATION, HFH4_01, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GOBP_POSITIVE_REGULATION_OF_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_PROTEIN_K48_LINKED_UBIQUITINATION, GOBP_PROTEIN_CATABOLIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN

GO Biological Process (6): ubiquitin-dependent protein catabolic process (GO:0006511), Wnt signaling pathway (GO:0016055), protein autoubiquitination (GO:0051865), protein K48-linked ubiquitination (GO:0070936), positive regulation of canonical Wnt signaling pathway (GO:0090263), protein ubiquitination (GO:0016567)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), poly-ADP-D-ribose binding (GO:0072572), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signal Transduction	2
Signaling by WNT	1
TCF dependent signaling in response to WNT	1
Deubiquitination	1
PTEN Regulation	1
Intracellular signaling by second messengers	1
Post-translational protein modification	1
Metabolism of proteins	1
PIP3 activates AKT signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
modification-dependent protein catabolic process	1
cell surface receptor signaling pathway	1
protein polyubiquitination	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
carbohydrate derivative binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1108 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF146	TNKS	O95271	907
RNF146	AXIN1	O15169	807
RNF146	TNKS2	Q9H2K2	792
RNF146	SH3BP2	P78314	769
RNF146	PARP1	P09874	706
RNF146	AXIN2	Q9Y2T1	682
RNF146	TRIP12	Q14669	605
RNF146	PARG	Q86W56	605
RNF146	APLF	Q8IW19	599
RNF146	CHFR	Q96EP1	565
RNF146	PARP10	Q53GL7	561
RNF146	BLZF1	Q9H2G9	549
RNF146	CASC3	O15234	547
RNF146	UBE2S	Q16763	517
RNF146	ECHDC1	Q9NTX5	507

IntAct

145 interactions, top by confidence:

A	B	Type	Score
RNF146	TNKS	psi-mi:“MI:0407”(direct interaction)	0.790
RNF146	TNKS	psi-mi:“MI:0915”(physical association)	0.790
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
PARP1	RNF146	psi-mi:“MI:0915”(physical association)	0.660
SDF4	ACAD11	psi-mi:“MI:0914”(association)	0.640
RNF146	DLG1	psi-mi:“MI:0407”(direct interaction)	0.590
RNF146	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.590
RNF146	PTPN13	psi-mi:“MI:0407”(direct interaction)	0.590
RNF146	MPP7	psi-mi:“MI:0407”(direct interaction)	0.590
RNF146	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
KASH5	RNF146	psi-mi:“MI:0915”(physical association)	0.560
RNF146	TUBGCP4	psi-mi:“MI:0915”(physical association)	0.560
TRAF2	RNF146	psi-mi:“MI:0915”(physical association)	0.560
RNF146	KASH5	psi-mi:“MI:0915”(physical association)	0.560
TUBGCP4	RNF146	psi-mi:“MI:0915”(physical association)	0.560
RNF146	Tnks	psi-mi:“MI:0407”(direct interaction)	0.440
MAST2	RNF146	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	RNF146	psi-mi:“MI:0407”(direct interaction)	0.440
RNF146	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
RNF146	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
RNF146	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (153): UBE2D3 (Biochemical Activity), UBE2D3 (Co-crystal Structure), TNKS (Reconstituted Complex), RNF146 (Biochemical Activity), UBE2D1 (Biochemical Activity), UBE2D2 (Biochemical Activity), UBE2D1 (Co-crystal Structure), RNF146 (Two-hybrid), RNF146 (Two-hybrid), CCDC155 (Two-hybrid), RNF146 (Affinity Capture-Western), XPC (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), LIG3 (Affinity Capture-MS), PARP2 (Affinity Capture-MS)

ESM2 similar proteins: A1YER5, A1YFY1, A2T6X5, A5PKK9, C0HBT3, D2H0Y8, E1B7Q7, E1B7X3, F1RCR6, G3X9J0, J7FCF0, O35730, O60292, O94972, Q06587, Q13064, Q14669, Q2PFU6, Q3T139, Q3TEL6, Q3UHH1, Q5DTT2, Q5REL3, Q5TCY1, Q5TJF3, Q5XIK5, Q60764, Q66JE4, Q6GQD5, Q6I6G8, Q6IEK5, Q6MGB6, Q6PCX9, Q76LL6, Q76N89, Q7L2J0, Q7ZUK0, Q8C120, Q8JZP9, Q8K3A9

Diamond homologs: C0HBT3, D2H0Y8, E1B7X3, O60683, Q11096, Q2PFU6, Q3T139, Q5REL3, Q5XIK5, Q66JE4, Q6FPI4, Q6GQD5, Q7ZUK0, Q8HXW8, Q9CZW6, Q9NTX7, A0A0R4IBK5, Q9SYU4, Q96LD4, A0A1L8FG46, A0A1L8FM16, B1AUE5, C0HKD7, O64425, P22681, P22682, P87176, P93030, Q09463, Q13191, Q1ACD5, Q28GL3, Q3TTA7, Q3UF64, Q587N7, Q5C8U1, Q5C8U3, Q5C8U4, Q5D7H8, Q5D7I2

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
RNF146	“down-regulates quantity”	AXIN1	ubiquitination
RNF146	“down-regulates quantity”	AXIN2	ubiquitination
RNF146	“down-regulates quantity”	GSK3B/Axin/APC	ubiquitination
RNF146	“down-regulates quantity”	TNKS	ubiquitination
RNF146	“down-regulates quantity”	TNKS2	ubiquitination
RNF146	“down-regulates quantity”	RNF146	ubiquitination
RNF146	“down-regulates quantity by destabilization”	AXIN1	ubiquitination
RNF146	“down-regulates quantity by destabilization”	AXIN2	ubiquitination
TNKS2	“up-regulates activity”	RNF146
TNKS	“up-regulates activity”	RNF146
RNF146	“down-regulates quantity by destabilization”	CASC3	ubiquitination
RNF146	“down-regulates quantity by destabilization”	BLZF1	ubiquitination
Ub:E2	“up-regulates activity”	RNF146	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Dopamine Neurotransmitter Release Cycle	5	38.2×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	35.1×	3e-10
Neurexins and neuroligins	11	33.3×	4e-12
Protein-protein interactions at synapses	7	28.6×	3e-07
RHOB GTPase cycle	5	11.9×	1e-03
RHOC GTPase cycle	5	11.3×	1e-03
RHOA GTPase cycle	6	6.9×	3e-03
Neuronal System	7	4.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	63.9×	1e-13
protein localization to synapse	6	50.5×	2e-07
receptor clustering	6	41.1×	6e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	38.1×	1e-07
protein-containing complex assembly	11	13.8×	1e-07
cell-cell adhesion	9	10.0×	2e-05
regulation of small GTPase mediated signal transduction	5	7.9×	8e-03
chemical synaptic transmission	7	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

52 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

895 predictions. Top by Δscore:

Variant	Effect	Δscore
6:127280227:GCA:G	acceptor_loss	1.0000
6:127280229:A:AG	acceptor_gain	1.0000
6:127280229:A:G	acceptor_loss	1.0000
6:127280230:G:GA	acceptor_gain	1.0000
6:127280230:GC:G	acceptor_gain	1.0000
6:127280230:GCA:G	acceptor_gain	1.0000
6:127280230:GCAC:G	acceptor_gain	1.0000
6:127280230:GCACA:G	acceptor_gain	1.0000
6:127280336:GAAAT:G	donor_gain	1.0000
6:127280338:AAT:A	donor_gain	1.0000
6:127280338:AATG:A	donor_loss	1.0000
6:127280339:AT:A	donor_gain	1.0000
6:127280340:TG:T	donor_loss	1.0000
6:127280341:G:GA	donor_loss	1.0000
6:127280341:G:GG	donor_gain	1.0000
6:127280342:TAAGT:T	donor_loss	1.0000
6:127280343:A:AG	donor_loss	1.0000
6:127266929:G:GT	donor_gain	0.9900
6:127280226:T:TA	acceptor_gain	0.9900
6:127280287:TG:T	donor_gain	0.9900
6:127280337:AAAT:A	donor_gain	0.9900
6:127286610:TCTTA:T	acceptor_loss	0.9900
6:127286611:CTTAG:C	acceptor_loss	0.9900
6:127286612:TTAG:T	acceptor_loss	0.9900
6:127286613:TA:T	acceptor_loss	0.9900
6:127286614:A:C	acceptor_loss	0.9900
6:127286615:G:GC	acceptor_loss	0.9900
6:127280344:A:AC	donor_loss	0.9800
6:127283907:G:GT	donor_gain	0.9800
6:127286614:A:AG	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000151823 (6:127275294 T>C), RS1000153927 (6:127285048 A>G), RS1000214790 (6:127285348 C>T), RS1000345693 (6:127267251 C>T), RS1000369053 (6:127277793 A>G), RS1000419295 (6:127266971 G>A,T), RS1000621882 (6:127265362 G>C,T), RS1000823072 (6:127278029 T>G), RS1001243671 (6:127271807 T>A), RS1001349632 (6:127268656 C>T), RS1001423214 (6:127268317 C>G), RS1001645569 (6:127274259 A>G), RS1001657207 (6:127281299 C>T), RS1001691948 (6:127271995 G>A), RS1001845180 (6:127273180 G>C,T)

Disease associations

OMIM: gene MIM:612137 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000162_1	Breast cancer	3.000000e-08
GCST001483_1	Intracranial volume	2.000000e-13
GCST002756_9	Subcortical brain region volumes	9.000000e-06
GCST003489_10	Food addiction	6.000000e-06
GCST003489_3	Food addiction	7.000000e-09
GCST005956_74	Waist-to-hip ratio adjusted for BMI	2.000000e-15
GCST005958_6	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-11
GCST005962_17	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-16
GCST006479_43	Diverticular disease	4.000000e-06
GCST011741_1	LDL cholesterol levels in HIV infection	6.000000e-06
GCST011741_15	LDL cholesterol levels in HIV infection	6.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004886	intracranial volume measurement
EFO:0007829	eating behaviour
EFO:0007830	food addiction measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009959	diverticular disease
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
butyraldehyde	decreases expression	1
coumarin	affects phosphorylation	1
pentanal	decreases expression	1
K 7174	increases expression	1
bazedoxifene	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
Fulvestrant	decreases methylation	1
Amiodarone	increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Vehicle Emissions	decreases reaction, decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	decreases expression	1
Lead	affects splicing	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Mifepristone	increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Amosite	increases methylation	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.